1. Field of the Invention
The present disclosure relates to modulating the function of hematopoietic stem cells using microRNAs. For example, hematopoietic output, such as blood output, hematopoietic engraftment, and development and progression of cancers of immunological origin can be modulated through microRNAs that are enriched in hematopoietic stem cells, such as miR-125b, miR-126 and miR-155.
2. Description of the Related Art
MicroRNAs (miRNAs) are a recently discovered class of small RNA molecules that are emerging as potent regulators of multiple aspects of cellular function. mRNAs are an evolutionally conserved class of small RNAs involved in post-transcriptional gene repression. See, e.g., Bartel, Cell 116, 281-97 (2004); Ambros, Nature 431, 350-5 (2004); Farh et al., Science 310, 1817-21 (2005). In animals, miRNAs are processed from larger primary transcripts (pri-miRNA or pri-miR) through an approximate 60-bp hairpin precursor (pre-miRNA or pre-miR) into the mature forms (miRNA) by two RNAse III enzymes Drosha and Dicer. See, e.g., Gregory et al., Nature 432, 235-40 (2004); Chendrimada et al., Nature 436, 740-4 (2005). The mature miRNA is loaded into the ribonucleoprotein complex (RISC), where it typically guides the downregulation of target mRNA through base pair interactions. Pri-miRNAs are transcribed by RNA polymerase II and predicted to be regulated by transcription factors in an inducible manner. Lee et al., Embo J 23, 4051-60 (2004); Fazi et al., Cell 123, 819-31 (2005); O'Donnell, et al., Nature 435, 839-43 (2005). While some miRNAs show ubiquitous expression, others exhibit only limited developmental stage-, tissue- or cell type-specific patterns of expression. See, e.g., Pasquinelli, Curr. Opin. Genet. Dev. 15, 200-5 (2005). In mammals, miRNAs have been associated with diverse biological processes, such as cell differentiation (Chen, Science 303, 83-6 (2004); Monticelli, et al. Genome Biol. 6, R71 (2005); Esau, et al., J. Biol. Chem. 279, 52361-5 (2004)), cancer (Calin, et al., Proc. Natl. Acad. Sci. USA 101, 2999-3004 (2004); Lu, J. et al., Nature 435, 834-8 (2005); He, L. et al., Nature 435, 828-33 (2005)), regulation of insulin secretion (Poy et al., Nature 432, 226-30 (2004)), and viral infection (Lecellier et al., Science 308, 557-60 (2005); Sullivan and Ganem, Mol Cell 20, 3-7 (2005)). Studies in plants have shown that miRNAs can be involved in the responses to a variety of environmental stresses.
Production of blood cells depends on proper hematopoietic stem-cell (HSC) function, which involves a delicate balance between HSC self-renewal and differentiation into progenitor populations. Several reports have found that miRNAs regulate the development of some hematopoietic lineages. O'Connell et al. Nat. Rev. Immunol. 10:111-122 (2010).